Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-29
2001-08-14
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S086000, C514S050000, C514S051000, C544S276000
Reexamination Certificate
active
06274589
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel L-&bgr;-Dioxolane Uridine nucleoside analogs and their use in the prevention and treatment of Epstein-Barr virus, Varicella-Zoster virus and Kaposi's Sarcoma virus, also known as HV-8.
BACKGROUND OF THE INVENTION
As human bacterial infections have become more manageable and treatable through the use of increasingly available antibiotic agents, viral infections have remained a more difficult and less treatable target. Emphasis in finding agents to treat viral infections has remained a high priority.
Epstein-Barr virus (EBV is an important human pathogen, related to herpes simplex virus (HSV). Elliot Kieff,
Virology
Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication. Chapter 74. Pp 2343-2396 and Alan B. Rickinson and Elliot Kieff,
Ibid.
Chapter 75, pp. 2397-2446. EBV is a lymphotrophic member of the genus Lumphocryptovirus, and belongs to the sub-family gammaherpesvirinae. Another new member of human virus also belonging to this family is Kaposi's sarcoma-associated herpes virus (KSHV/HHV8). Chang, et al.,
Science,
266:1865-1869 (1994); Cesarman, et al.,
N. Eng. J. Med.,
332:1186-1191 (1995); Soulier, et al.,
Blood,
86:1276-1280 (1995). There are two subtypes of EBV identified and their genomes are nearly identical, but there is no clear relationship between EBV associated diseases and EBV sub-types. Abdul-Hamid, et al.,
Virology,
190: 168-175 (1992) and Sample, et al.,
J. Virol.
64:4084-4092 (1990). The lytic EBV genome is a linear, double-stranded, 172 Kbp DNA composed of 60 mol % guanine and cytosine. The genome has been sequenced and it was found to be capable of encoding a number of virus specified proteins, which include several enzymes involved in virus DNA synthesis during lytic infection of EBV. In vitro, EBV infection is generally limited to B-lymphocytes, although epithelial cells can also be infected. Sixbey, et al.,
Nature,
306:480-483 (1983). In humans, the virus genome can be detected in B-lymphocytes and T-lymphocytes as well as epithelial cells. The EBV genome replicates lytically in the linear form and can also be latent as supercoiled circular DNA. The expression of the EBV genome in lytic infected cells is very different from latent infected cells. EBV specified DNA plymerase, Dnase and dTbd kinase are only expressed in cells upon lytic DNA replication. Cell culture studies indicated the essential role of EBV specified DNA polymerase for EBV DNA replication during lytic infection, but not for the maintenance of supercoiled EBV DNA in latent infected cells. A unique set of EBV proteins including EBVNA 1 and sometimes, EBNA LP, 2, 3A, 3B, 3C, LMP1 as well as LMP2 is expressed in latent infected or transformed cells. Elliot Kieff,
Virology,
Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication. Chapter 74. Pp 2343-2396 and Alan B. Rickinson and Elliot Kieff,
Ibid.
Chapter 75, pp. H2397-2446.
Structurally, EBV is similar to that of other herpes viruses—it has a double-stranded DNA genome contained within a nucleocapsid, which is surrounded by a lipid envelope containing viral glycoproteins. A tegument protein occupies the space between the envelope and the gucleocapsid.
While primary EBV infection in infancy appears to be almost asymptomatic, a proportion (in some studies up to 50%) of serologically confirmed primary infections in adolescence or early adult life are manifested as infectious mononucleosis (IM) also called the “Kissing Disease”. Transmission of EBV is primarily through the saliva, although some infections are transmitted via blood transfusions. A high percentage (>85%) of patients in the acute phase of infectious mononucleosis secrete EBV. In the mid-1970's, EBV was identified to cause fatal IM/X-linked lymphoproliferative syndrome (XLP) in young male children who had X-linked immunodeficiency. Sullivan and Wood, (
Immunodeficiency Rev.
1:325-347 (1989). Fatal EBV infection is also found to be associated with nonfamilial monophagocytic syndrome (VAHS) for which there is no effective therapy. Alan B. Rickinson and Elliot Kieff,
Virology,
Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication, Chapter 75, pp. 2397-2446 and Craig, et al.,
Am. J. Clin. Path.,
97:189-194 (1992).
Epstein-Barr virus is also recognized as a causative agent of B-cell proliferative diseases, and is linked to a variety of disease states, including a rare progressive mononucleosis-like syndrome and oral hair leukoplakia in AIDS patients. EBV has also been associated with certain types of cancer such as Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, EBV-associated T-cell lymphoma and nasal T-cell lymphoma. Certain patients, in particular, those with suppressed immune systems such as AIDS patients and organ transplant patients who are being treated with immunosuppressive agents, are particularly susceptible to EBV manifestations, especially the development of EBV-associated lymphomas.
Chu, et al., in PCT application PCT/US95/01253, describe a number of L-nucleoside analogs for use in the treatment of Hepatitis B virus and Epstein-Barr virus infections. One agent disclosed in the PCT application, 2′-fluoro-5-methyl-&bgr;-L-arabinofuranosyluridine (L-FMAU), showed good activity against EBV. Noteworthy is the fact that when a 5-methyl group of L-FMAU was substituted with a bromo group, the anti-EBV activity decreased.
Several compounds have been shown to have activity against EBV replication in culture at concentrations non-toxic to cell growth. These include acyclovir (ACV), gancyclovir (DHPG), pencyclovir, D-FMAU and its analogs, 5-bromovinyl dUrd, phosphonoformate and phosphorothioate oligonucleotides. See Lin, et al.,
Antimicrob. Agents and Chemo.
(February) 32(2):265-267 (1988); Lin, et al.,
Antimicrob. Agents and Chemo.,
32(7):1068-1072 (1988); Cheng, et al.,
Proc. Natl., Acad. Sci. USA,
80:2767-2770(1983); Datta, et al.,
Proc. Natl., Acad. Sci. USA,
77:5163-5166 (1980); Datta, et al.,
Virology,
114:52-59 (1981); Lin, et al.,
Antimicrob. Agents and Chemo.,
31:1431-1433 (1987); Olka and Calendar,
Virology
104:219-223 (1980); Lin, et al.,
J. Virol.,
50:50-55 (1984); Yao, et al.,
Antimicrob. Agents and Chemo.
37:1420-1425 (1993) and Yao, et al.,
Biochem. Pharm., (
51):941-947(1966).
OBJECTS OF THE INVENTION
It is an object of the present invention to provide compounds, pharmaceutical compositions and methods of treating and/or preventing Epstein-Barr virus, Varicella-Zoster virus and Kaposi's Sarcoma virus (HV-8) infections in patients.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to the discovery that certain &bgr;-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV) and Kaposi's Sarcoma virus (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue).
Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of EBV, Varicella-Zoster virus and Kaposi's Sarcoma virus (HV-8). Certain of these agents also may be useful for inhibiting the growth or replication of other viruses (for example, HSV) or for treating other viral infections and/or related disease states. Other agents may be used as biological probes for testing purposes or as intermediates in the synthesis of related nucleoside compounds having pharmacological activity.
Compounds of the present invention find particular use in combating viral infections which afflict animals, and in particular, humans suffering from Epstein Barr virus, Varicella-Zoster virus and Kaposi's Sarcoma vir
Cheng Yung-Chi
Chu Chung K.
Qu Fucheng
Coleman Henry D.
Crane L E
Geist Gary
Sudol R. Neil
Yale University
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